16-alkenyl and 16-alkynylestratriene-3,16,17-triols and ethers thereof



United States Patent 3,002,008 IG-ALKENYL AND lfi-ALKYNYLESTRATRIENE-3,16,17-TRIOLS AND ETHERS THEREOF David A. Tyner, Glenview, IlL,assignor to G. D. Searle & Co., Chicago, 111., a corporation of DelawareNo Drawing. Filed Aug. 16, 1960, Ser. No. 49,815 7 Claims. (Cl.260-3975) The present invention relates to compounds of' the formula OHp Z wherein R is an alkyl radical, R is a hydrogen or alkyl radical andZ is an alkenyl or alkynyl radical. Among the alkyl radicals representedby R and R, especially lower alkyl radicals are preferred, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl,pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, heptyl andoctyl. Among the alkenyl and alkynyl radicals represented by Z,especially lower alkenyl and lower alkynyl radicals are preferred, forexample, any radical derived from those recited above by replacement01f1 single bonds by multiple bonds in the carbon atom c am.

The compounds of the present invention are prepared by a route whichbegins with 16-keto estradiol and its 3-(lower alkyl) ethers. Thel7-hydroxy group is protected by ether formation, conveniently as alower alkyl or pyranyl ether, and the ketone is condensed with an organometallic derivative of a lower alkene or lower alkyne. The protectingether group is optionally removed.

The compounds of this invention possess valuable pharmacologicalproperties. They are highly potent agents in causing the decrease ofserum cholesterol concentration and the correspondingcholesterol/phospholipid ratio; they also possess a remarkedly lowestrogenic potency.

3,002,008 Patented Sept. 26, 1961 solution is chilled. The precipitatewhich forms is removed by filtration to give3-methoxy-1,3,5(10)-estratrien-17B-ol16-one pyranyl ether, melting at117-130. To 300 parts of tertiary butyl alcohol is added 11.5 parts ofpotassium, and the resultant solution of potassium tertiary butoxide issaturated with acetylene. To the solution thus obtained at 5 is added asolution of 11.4 parts of 3-methoxy-l,3,5(l0)-estratrien-l7/3-ol-l6-onepyranyl The following examples describe in detail certain of thecompounds illustrative of the present invention and methods which havebeen devised for their manufacture. However, the invention is not to beconstrued as limited thereby, either in spirit or in scope, since itwill be apparent to those skilled in the art of organic synthesis thatmany modifications, both of materials and of methods, may bepracticed'without departing from the purpose and intent of thisdisclosure. In the examples hereinafter detailed, temperatures are givenin degrees centigrade, pressures in pounds per square inch, and relativeamounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 ether in 50 parts of dioxane. The clear yellow solution thusobtained is stirred at 5-10 for about 5 hours in an acetyleneatmosphere, and then diluted to a volume of 1 liter with ice cold water.The precipitate which forms is removed by filtration and washed withwater to give the l7-pyranyl ether of 3 methoxy-l6u-ethynyl-l,3,5(10)-estratrienel6l3,l7;3-diol, melting at 152l60. A'mixture of 10 par-ts ofthe acetylenic ether, parts of methanol and 0.5 part of hydrochloricacid is heated under reflux for 2 minutes and then diluted with 100parts of hot water. On cooling to room temperature, the reaction mixturedeposits a solid, which is removed by filtration and recrystallized fromaqueous ethanol to give 3-.methoxy-16a-ethynyl-1,3,5 l0)-estratriene'16l9,17fl-diol melting at 190-194".

EXAMPLE 2 3 ethoxy 160a ethynyl 1,3,5(10) eutratriene-165,17,8-di0l.-Substitution of parts of 3-ethoxy-l,3, 5(10)-estratrien-17,8-01-16-one for the 3-methoxy-1,3,5(10)-estratrien-l7B-ol-16-one of the preceding Example 1 gives by theprocedure therein detailed 3-ethoxy-l6uethynyl-1,3 ,5 10)-estratriene16[3,17 3-diol.

EXAMPLE 3 3,175 dimethoxy 16cc ethynyl 1,3,5(10)estratrien-I6,8-0l.Substitution of 11 parts of3,17,8-dimethoxy-1,3,5(10)-estratrien-16-one for the 3-methoxy-1,3,5(10)-estratrien-l6-one pyranyl ether of Example 1 gives by theprocedure therein detailed3,l7B-dimethoxy-16aethynyl-l,3,5(10)-estratrien-l6B-ol, melting at about165- EXAMPLE 4 3,175 diethoxy 16a ethynyl 1,3,5(10)estratrien-l6fi-ol.-Substitution of 12 parts of 3,17B-diethoxy-1,3,5(10)-estratrien-l6-0ne for the 3-methoxy-1,3,5(l0)-estratrien-l6-one pyranyl ether of Example 1 gives by the proceduretherein detailed 3,l7p-diethoxy-l6a-ethynyl-1,3,5 l0)-estratrien-l6fi-ol.

EXAMPLE 5 3 methoxy 16a (1 octynyl) 1,3,5(10)estratriene-166,17B-diol.-To a solution of 11.3 grams of ethylmagnesiumbromide in ethyl ether is added portionwise 10.4 parts of l-octyne in 35parts of dry ether. After the addition is completed, the solution isrefluxed for 2 hours and then added portionwise to a solution of 5 partsof 3-methoxy-17B-hydroxy-1,3,5(10)-estratrien-16- one in 45 parts ofbenzene. The mixture is then refluxed for 6 hours. To this mixture areadded 4.8 parts of acetone in 16 parts of benzene at a temperature ofabout 60 C. After chilling, the mixture is hydrolyzed with saturatedaqueous ammonium chloride. The layers are separated, and the organiclayer is evaporated. The oily residue is recrystallized twice fromcyclohexane to yield 3 methoxy 16a (1 octynyl) 1,3,5(10) estratriene-16,8,17B-diol melting at about -132 C.

EXAMPLE 6 3,175 dimethoxy 16oz (1 octynyl) 1,3,5(10)-estratrien-J6B-0l.--Substitution of 5 parts of 3,17,8-dimethoxy-1,3,510)-estratrien-16-one for the3-methoxyl7fl-hydroxy-1,3,5(10)-estratrien-16-one of Example 5 gives bythe procedure therein detailed 3,17/3-dimeih0xy- 16a-( l-octynyl)-1,3,510)-estratn'en-16flol.

EXAMPLE 7 3,176 diethoxy 16a (1 octynyl) 1,3,5(])estratrien-I6/3-0L-Substitution of parts of3,17/3-diethoxy-1,3,5()-estrat1ien-16-one for the3-methoxy-l7phydroxy-1,3,5(10)-estratrien-l6-one of Example 5 gives bythe procedure therein detailed 3,17/3-diethoxy-16a-(1- octynyl) -l,3,5(10) -estratrien-16;3-ol.

EXAMPLE 8 3 methoxy 16oz vinyl 1,3,5(10) estratrien 16,6, I7B-dioL-Amixture of 4 parts of3-methoxy-16u-ethynyl-l,3,5(10)-estratriene-16,3,17/3-diol, 200 parts ofpyridene, 50 parts of dioxane and 0.1 part of 10% palladiumon-charcoalis treated with hydrogen at atmospheric pressure for 1 hour. Theresultant mixture is subjected to filtration, and the filtrate isevaporated to dryness. The residue is recrystallized from methanol andthen from aqueous ethanol to give 3-methoxy-16u-vinyl-1,3,5(10)-estratriene-16 3,17}3-diol, melting at about 99-100.

EXAMPLE 9 3,175 dimethoxy 16a vinyl 1,3,5(10)estratrienldfl-oL-Substitution of 4 parts of3,l7,B-dimethoxy-16aethynyl-1,3,5(10)-estratrien-16B-ol for the3-methoxy- 16a-ethynyl-1,3,5 l0)-estratriene-16/8,17B-diol of Example 8gives by the procedure therein detailed 3,17fi-dimethoxy-l6u-vinyl-1,3,5l0)-estratrien-165-ol.

EXAMPLE 10 3,17 3 diethoxy 16a vinyl 1,3,5(10) estratrien-I6B-oL-Substitution of 12 parts of3,17-diethoxy-16aethynyl-1,3,5(10)-estratrien-l6fl-ol tor the 3-methoxy-16u-ethynyl-1,3,5 (10)-estratriene-165,175-diol of Example 8 gives bythe procedure therein detailed 3,17/3-diethoxy-16a-vinyl-1,3,5 10)-estratrien-1 618-01.

EXAMPLE ll 3 methoxy 16oz allyl 1,3,5(10) estratriene 16B, J7B-di0l.-Toa solution of 5 parts of3-methoxy-17flhydroxy-1,3,5(10)-estratrien-l6-one in 22 parts of benzenethere is added in the course of 3-5 minutes a solution of allylmagnesium bromide prepared from 18.4 parts of magnesium, 7.6 parts ofallyl bromide and 35 parts of anhydrous ether. The resulting mixture isheated at reflux temperature for 12 hours, cooled to about 50 C. andthen treated with 3 parts of acetone and 9 parts of benzene. Thismixture is cooled in an ice bath while 10 on p Z wherein R is a memberof the class consisting of hydrogen and lower alkyl, R is lower alkyl,and Z is a member of the class consisting of lower alkenyl and loweralkynyl.

2. A compound of the formula (lower alkenyl) (lower alkyl) 0 3. 3methoxy 16oz vinyl 1,3,5(10) estratriene- 16,3,17/3-di0l.

4. 3 methoxy 16a-allyl 1,3,5(l0) estratriene- 1613,17 8-diol.

5 3,17 3 dimethoxy 16a ethynyl 1,3,5(10) estratrien-16fi-ol.

6. 3 methoxy 16a ethynyl 1,3,5 (10) estratriene- 165,1718-diol.

7. 3 methoxy 16o: (1 octynyl) l,3,5(l0) estratriene-16 8,17fi-diol.

No references cited.

1. A COMPOUND OF THE FORMULA